tbuckley/cabot-search huggingface dataset:
Frequency and outcomes of molecularly guided off-label targeted agent prescriptions in the VA National Precision Oncology Program (NPOP).
Authors: Vishal Vashistha, Aixia Guo, Evangelia Katsoulakis, Meghan Price, Sara Ahmed, Michael J. Kelley
Journal: Journal of Clinical Oncology (2022)

e18676 Background: The increasing availability of comprehensive genomic profiling (CGP) and a growing number of targeted agents (TAs) has led to substantial improvements in outcomes among cancer pts with actionable mutations. CGP has led to identification of both on-label (level 1) variants, for which TAs have known efficacy, and off-label variants with lesser strength of supporting data. We sought to evaluate real-world prescription patterns and outcomes of off-label TA prescriptions among pts who underwent CGP. Methods: The NPOP database and VA Corporate Data Warehouse were queried to identify pts who had underwent CGP between February 2019 and December 2021 and were prescribed at least 1 of 73 TAs before January 2022. TAs prescribed for FDA-approved indications not relying on CGP as a companion diagnostic were excluded. OncoKB was used to annotate gene variants and evaluated against prescriptions to select pts who received off-label TAs. The frequency of off-label TA use, and for those treated &gt; 4 weeks, rate of pts treated for 6 months or longer, median treatment duration and overall survival (OS) were computed. Results: Of the 18686 patients who underwent CGP, 2107 (11%) were prescribed any TA, and 191 (1%) were prescribed off-label TAs, with 31 receiving multiple concurrent or sequential off-label TAs. Mean age was 65.5 years, and 88% were male. TAs were most often prescribed for cancers of unknown primary (CUP, 29), NSCLC (24), and colorectal cancer (22). Frequency of off-label prescriptions was highest for pts who completed CGP for thyroid cancer (9%), breast cancer (8%), and CUP (2%). Most common variants involved BRAF (21%), ERBB2 (18%), BRCA1/BRCA2/ATM (9%), and PIK3CA (6%). Among all 164 pts treated &gt; 4 weeks, 40% received TAs for 6 months or longer, including 50%, 47%, and 46% of pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease, respectively. Median therapy duration and OS was 141 [78.5 – 317, IQR] days and 181 [96.5 – 304.5, IQR] days, respectively. Conclusions: Though overall use of off-label TAs following CGP is low, nearly 10% of advanced thyroid and breast cancer patients are prescribed TAs for off-label indications. Forty percent of all pts receiving off-label TAs continue for at least 6 months, with higher rates for pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease. CGP-guided off-label treatment approaches offer unique options for advanced stage cancer with amenable molecular profiles.
Symptom monitoring with patient-reported outcomes using a web app with alerting algorithms among patients with lung cancer (SYMPRO-Lung).
Authors: Annemarie Becker-Commissaris, Nicole Erica Billingy, Rianne Hoek, Vashti Tromp, Corina van den Hurk, Iris Walraven
Journal: Journal of Clinical Oncology (2022)

12060 Background: The use of patient reported outcomes (PROs) to monitor symptoms during and after cancer treatment can improve symptom management, health-related quality of life (HRQoL), and overall survival, especially when linked to an alert system. Previous studies used alerts to the health care provider (HCP), but will this also work when patients receive the alerts? The aim is to compare a reactive (patient receives alert) and an active (HCP receives alert) method of PRO symptom monitoring on symptom incidence and management during the first 15 weeks of treatment. Methods: SYMPRO-Lung is a Dutch multicenter stepped wedge RCT performed among lung cancer (LC) patients to monitor symptoms, using a PRO-CTCAE LC subset. The NCI scoring algorithm assessed the symptom severity. If symptoms exceeded a predefined threshold an alert was sent by email to the HCP (active arm) or to the patient (reactive arm). Differences between both study arms in baseline characteristics, symptom incidence and management, were assessed using chi-square tests. Results: In total, 244 patients (active arm n = 155, 64%, reactive arm n = 89, 37%) completed 2412 symptom checklists during the first 15 weeks of treatment, with a mean of 10 per patient (pp) (SD 4.3). A total of 673 alerts (28%) were triggered, with a mean of 3 (SD 2.1) pp in both arms. The top 3 symptoms that caused the app to send an alert were fatigue (n = 231, 19%), pain (n = 188, 16%), and constipation (n = 144, 12%). Decreased appetite, diarrhea, and nausea were significantly higher in the reactive arm compared to the active arm (see table). For 313 alerts (74%), telephone contact with a HCP was the only intervention needed. 57 Alerts (13%) were discussed during a planned outpatient’s consultation in the week of the alert. For 39 alerts (9%) the patients were referred to another specialty (see table). However, ‘no need to follow-up’ (FU) was requested after 237 alerts (35%). For all symptoms, the no FU request was significantly higher in the reactive arm (n = 135, 32% vs n = 102, 40%), compared to the active arm (p-values between 0.02 and &lt; 0.001). Conclusions: In both arms an average of 3 alerts pp were triggered. In the reactive arm, significantly more patients chose not to contact their HCP compared to the active arm. Future research needs to unravel the underlying mechanisms and the potential consequences of this observed difference between study arms. Clinical trial information: Trial NL7897. [Table: see text]
Accuracy of magnetic localisation device placement and retrieval in breast cancer patients from a single internationally accredited breast center in Johannesburg, South Africa.
Authors: Carol Benn, Dominic van Loggerenberg
Journal: Journal of Clinical Oncology (2022)

e18697 Background: A variety of techniques are used to localise breast cancers prior to breast surgery. One such technique involves the placement of a magnetic device (Magseed). the magnetic device placement data from one radiology unit in a multi-disciplinary unit consisting of 4 radiology units over a 6 month period which sees 450 newly diagnosed breast cancer patients per year and places with over 360 Magseeds in a 6 month period. The aim of the study was to conduct a review of Magseed placement and ease and efficacy of retrieval across varying depths within the breast. Methods: The device used and analyzed in this study is constructed of medical-grade stainless steel magnetized, 1x5mm in size and can be implanted long term. The seeds were placed both under ultrasound guidance and stereotactically, there were no complications at the time of placement. Post-placement ease of localization and retrieval of the Magseed Measurements of distances from the nearest perpendicular skin surface was provided by the radiologist. markers were assessed by confirmation of the presence of the Magseed(s) in the specimen through the use of the Sentimag probe and confirmation visualized by intraoperative radiology and intra-operative pathology. Results: All of the seeds were localised during surgery and retrieved without difficulties reported by surgeons. The use of intraoperative radiology confirmed retrieval of all seeds in all patients. The minimum placement depth was 8.33mm, the maximum placement depth was 87mm and the average placement depth was 47mm. The placement of the seeds were place over a range of times before surgery, from 3 days prior to surgery to up to 249 days. Localisation was 100% successful using the Sentimag probe in theatre, and the retrieval rate was 100% across the full 368 analyzed patient set. . Radiological confirmation of the Magseed placement was confirmed through the use of an intraoperative radiological Biovision machine. Our data shows that Magseeds can be placed across a wide range of breast sizes and at variable depths with no complications or difficulty experienced during intraoperative localization and retrieval of the seeds. Conclusions: The data collected, and the demographic analyzed, shows that magnetic marker placement and retrieval is possible across a wide range of depths in the breast with no complications arising in radiological placement and intraoperative localisation and retrieval. Surgeons reported ease of transcutaneous localisation. A 100% retrieval rate was reported. In all cases, clear margins were achieved with: aid from audio and visual confirmation from the Sentimag probe; intraoperative radiology and intraoperative pathology.
A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors.
Authors: Jian Li, Jun Zhao, Baoshan Cao, Jian Fang, Xiaoyan Li, Mengzhao Wang, Yi Ba, Xingya Li, Zhihua Li, Zhe LIU, Yongsheng Wang, Ying Cheng, Chunmei Bai, Lin Shen
Journal: Journal of Clinical Oncology (2022)

3089 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancer (NSCLC), 1-2% of colorectal cancer (CRC) and other solid tumors in China. JAB-21822 (Jacobio, Beijing, PRC) is a highly selective, covalent oral inhibitor of KRAS G12C. Methods: NCT05009329 is an ongoing first-in-human, open label phase I/II study of JAB-21822 in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of JAB-21822. Other objectives include preliminary efficacy, pharmacokinetics, and biomarkers. Here we report the results from the dose escalation phase of the trial. Results: As of January 28th, 2022, 53 patients with a median age of 62 years (39-79) were enrolled in 5 different dose levels: 200mg QD, 400mg QD, 800mg QD, 400mg BID and 400mg TID. Most patients (55%) had ≥ 2 prior lines of therapy. No dosing-limiting toxicities were observed. Two treatment-related adverse events (TRAEs) were G4 neutropenia (1 in 400mg BID and 1 in 400mg TID). The most common TRAEs (≥ 10%) included anemia (24.5%), total bilirubin increase (20.8%), direct bilirubin increase (15.1%), proteinuria (13.2%) and indirect bilirubin increase (11.3%). Only Grade 1 and 2 TRAEs were observed in the QD cohorts. A total of 33 patients (22 NSCLC, 9 CRC and 2 pancreatic cancer) had at least 1 post-baseline tumor assessment; in the 800mg QD cohort, overall response rate (ORR) and disease control rate (DCR) were 50% (5/10) and 100% (10/10), respectively, including 4 non-confirmed partial response (PR); in the 400mg QD cohort had an ORR and DCR of 80% (4/5) and 100% (5/5) respectively, including 2 non-confirmed PR. Patients with NSCLC (400mg QD and 800mg QD), the ORR and DCR were 70% (7/10) and 100% (10/10), respectively, including 5 non-confirmed PR. With respect to the pharmacokinetics analysis, JAB-21822 was rapidly absorbed with an average T max of 2 hr and reached higher plasma exposures (C max and AUC 0-24h ) after a single dose and multiple doses at C1D8. Conclusions: JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing. Clinical trial information: NCT05009329.
Risk, overall survival, and prognostic analysis of therapy-related acute myeloid leukemia in non-Hodgkin lymphoma survivors.
Authors: Utsav Joshi, Suman Gaire, Adheesh Bhattarai, Vishakha Agrawal, Bishesh Sharma Poudyal, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2022)

e19037 Background: Therapy-related acute myeloid leukemia (tAML) is a serious complication in patients with Non-Hodgkin lymphoma (NHL) exposed to chemotherapy or radiation. tAML demonstrates high risk characteristics and poorer outcomes compared with de novo AML. We aimed to quantify the risk of tAML in NHL, determine factors associated with overall survival (OS) in tAML, and compare them with de novo AML. Methods: Patients with a histologic diagnosis of NHL and de novo AML from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) 18 database. AML that developed at least 1 year after the diagnosis of NHL was classified as tAML. Multiple primary standardized incidence ratio (SIR) sessions of the SEER*Stat software (version 8.3.9) were used to calculate SIR and absolute excess risk (AER) of tAML based on - age, sex, race, year of diagnosis, chemotherapy, radiotherapy, and interval from NHL diagnosis. The 95% confidence intervals (CI) and p-values were generated using multivariate Poisson regression model. OS of both tAML and de novo AML was assessed using Kaplan Meier curves and then compared using log rank test. The roles of various factors on OS in tAML and de novo AML were evaluated using multivariate cox proportional hazard regression. Results: A total of 373 patients with tAML (N for NHL = 301,903) and 23,360 patients with de novo AML were included in the analysis. More de novo AML cases were ≥70 years compared to tAML (41.1% vs 32.7%, p &lt; 0.001). The risk of development of tAML was significantly higher in ages &lt; 60 years compared to 60-69 years and ≥70 years (SIR 14.0, 95% confidence interval [CI] 11.79-16.51 vs SIR 4.87, 95% CI 4.00-5.86 vs SIR 2.80, 95% CI 2.32-3.34, p &lt; 0.0001). Patients who received chemotherapy were more likely to develop tAML than the non- recipients (SIR 8.44, 95% CI 7.51-9.44 vs SIR 1.75, 95% CI 1.37-2.21, p &lt; 0.0001). The risk of tAML was higher within 5 years of NHL diagnosis (SIR 5.05, 95% CI 4.49-5.67 vs SIR 4.39, 95% CI 3.49-5.45, p &lt; 0.001). There was no statistically significant difference in SIR based on sex, race, receipt of radiotherapy, and year of diagnosis. The median OS and 5-year OS were- 8 months and 13.1% for tAML and 10 months and 27.6% for de novo AML. On multivariate analysis, tAML was not found to be an independent predictor of OS (HR 0.93, 95% CI 0.82-1.04, p = 0.21). Age ≥60 years (age 60-69 years: HR 1.53, 95% CI 1.08-2.15, p = 0.01, age ≥70 years: HR 1.93, 95% CI 1.40-2.66, p &lt; 0.001) and no chemotherapy (HR 1.82, 95% CI 1.40-2.35, p &lt; 0.001) were associated with poor OS in tAML subcategory. Conclusions: Our large population-based study shows increased risk of tAML within the first 5 years of NHL diagnosis, younger NHL survivors, and chemotherapy recipients. Older age and no chemotherapy predispose to dismal OS in tAML.
Analysis of molecular characterization: Pancreatic ductal adenocarcinoma with hepatic metastases.
Authors: Yonggang He, Xiaobing Huang, Jing Li, Yichen Tang, Pengyao Du, Yaxuan Zhang, Chuang Liu, Ling Li
Journal: Journal of Clinical Oncology (2022)

4129 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Distant metastasis is the leading cause of cancer death. Approximately 50% of PDAC patients are discovered to have distant metastases, mainly in the liver. Chemotherapy is the main recommended treatment for metastatic PDACs, with a median survival time of only 4-6 months and the 5-year survival of 1%. Therefore, deciphering the molecular mechanisms of metastatic PDAC is urgently for exploring effective therapeutic targets. Methods: 93 normal-paired samples from patients with PDAC were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: A total 93 patients with PDAC were analyzed, including hepatic metastases (15/93), lymph node metastases (1/93), colon metastases (1/93), pelvic metastases (1/93), and no distant metastasis (75/93). In PDAC patients without distant metastasis, the most frequent mutated gene was KRAS (72%), followed by TP53 (60%), CDKN2A (21%), SMAD4 (17%), ARID1A (11%), RNF43 (9%), and RBM10 (8%). In PDAC patients with hepatic metastases, we found that the most frequent one was KRAS (100%), followed by TP53 (87%), CDKN2A (40%), SMAD4 (40%), RNF43 (13%), and RBM10 (6%). Furthermore, four PDAC patients occurred KRAS copy number amplification, including 2 cases of hepatic metastases. And a hepatic metastases PDAC patient had ERBB2 and MET copy number amplification. We also found that seven no-metastasis patients carried pathogenic or likely pathogenic germline variants, including BRIP1, PALB2, RECQL, ATM, RAD50, FANCM and BRCA1. Conclusions: High frequency mutation genes in PDAC patients with hepatic metastases were highly consistent with those of no-metastasis patients. KRAS and TP53 gene co-mutations were extensively mutated in hepatic metastases patients. Our results revealed the molecular mechanisms driving PDAC hepatic metastases should be considered in further study.
Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Susan Halabi, Akash Roy, Larysa Rydzewska, Peter Godolphin, Mahesh K. B. Parmar, Maha H. A. Hussain, Catherine Tangen, Ian Thompson, Wanling Xie, Michael Anthony Carducci, Matthew Raymond Smith, Michael J. Morris, Gwenaelle Gravis, David P. Dearnaley, Paul Verhagen, Takayuki Goto, Nicholas D. James, Marc E. Buyse, Jayne F. Tierney, Christopher Sweeney
Journal: Journal of Clinical Oncology (2022)

5006 Background: We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration. Methods: We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS. Results: IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS. Conclusions: Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several. [Table: see text]
Demographic differences in the treatment of gastric cancer.
Authors: Michael Brian LaPelusa, Chan Shen, Michael K. Gibson, Erin Alexis Gillaspie, Eric Lambright, Anuradha Bapsi Chakravarthy, Cathy Eng
Journal: Journal of Clinical Oncology (2022)

e16078 Background: Globally, as of 2020, gastric cancer is the 5 th most common cancer and the 4 th common cause of cancer-related death. Our objective is to determine how gender/sex, race, treatment location, and socioeconomic factors contribute to the treatment of patients (pts) with gastric cancer. Methods: 233,479 pts were identified from the National Cancer Database (NCDB) between 2004 and 2018. Pts were divided into 3 age-based subgroups. The &lt;=45 y/o (N=14,481) group was designated early-onset gastric cancer (EOGC). The 46 - 70 y/o (N=118,756) group was termed average-onset gastric cancer (AOGC). The &gt;70 y/o (N=100,242) group was termed late-onset gastric cancer (LOGC). Overall 114,117 (48.9%) received surgery; 112,953 (48.4%) received chemotherapy; and 55,024 (23.6%) received radiation therapy. Unfortunately, data were not available on the receipt of bimodal or trimodal therapy. We used chi-square tests and a logistic regression model to examine factors associated with treatment patterns. Factors considered in the model included: age, gender/sex, race/ethnicity, cancer stage, facility type, year of diagnosis, insurance status, and location of residence. Results: Females represented a higher proportion of EOGC pts (47%) compared to AOGC pts (34.5%) and LOGC pts (41%). A greater amount of EOGC pts were Hispanic (24.9%) compared to AOGC pts (10.4%) and LOGC pts (7.1%). EOGC pts were often treated at academic centers (65.8%) compared to AOGC pts (60.9%) and LOGC pts (54.4%). A larger percentage of EOGC pts were uninsured (11.7%) vs AOGC pts (5.4%) and LOGC pts (0.9%). The table outlines differences in treatment by age, sex, race/ethnicity, facility type, year of diagnosis, insurance, and location of residence (after adjusting for stage). Conclusions: EOGC pts display unique demographic characteristics. After adjusting for stage, significant differences exist in how pts with gastric cancer are treated. Further work is needed to delineate the impact of gastric cancer in young pts and determine which factors play a role in treatment for pts of all ages from both the patient and oncologist perspective.[Table: see text]